1. Field of the Invention
The present invention relates to pyripyropene A derivatives having an extremely good inhibitory activity against cholesterol acyltransferase isozyme 2 (hereinafter abbreviated as ACAT2). More particularly, the present invention relates to pyripyropene A derivatives in which one or both of the 1- and 11-positions are substituted by an acyloxy group other than acetoxy group, the 11-position is substituted by carboxyl, an alkoxycarbonyl, or an arylcarbamoyl group, or the 1- and 11-positions are substituted by a cyclic acetal group.
2. Background Art Description of Related Art
The number of patients in Japan with hyperlipemia or arteriosclerosis which are associated with a high risk of high-mortality diseases such as myocardial infarction and cerebral apoplexy is said to be as many as thirty million, including subjects having no subjective symptoms. Even at the present time when the Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases have been revised by the Japan Atherosclerosis Society, death due to these diseases ranks high among the causes of death in Japan. Hyperlipemia and arteriosclerosis are significant health problems not only in Japan but also in Europe and the Americas.
The drugs which are most widely used at present for prevention and treatment of arteriosclerosis are statin drugs which specifically inhibit hydroxy-3-methylglutaryl coenzyme A (hereinafter abbreviated as HMG-CoA) reductase. Statin drugs have been the most widely sold drugs in the world for 8 consecutive years from 2001. They are widely used, as demonstrated by the fact that two statin drugs ranked in the top thirty drugs having the highest worldwide sales in 2008. However, in actuality, it has been found that these drugs exhibit an effect on prevention of onset in only 30%-40% of patients and produce no suppression of cardiovascular diseases or the like in about half of patients who received therapy with such a drug (Non-Patent Document 1).
The reasons why HMG-CoA reductase inhibitors which are currently used as prophylactic or therapeutic agents for arteriosclerosis cannot sufficiently suppress cardiovascular diseases or similar diseases are thought to relate to the fact that the mechanism of onset of arteriosclerosis is complicated, the onset mostly being caused by heredity, diabetes, drugs, and other various factors acting in combination. Therefore, diagnosis and treatment of these diseases need to be based on the pathological conditions of each patient.
Accordingly, there is an urgent desire for the development of a drug having a new mechanism of activities which can be expected to have an effect on suppression of onset of disorders in the coronary artery or degeneration of lesions in the coronary artery and which is different from the mechanism of statin drugs. However, there has been almost no progress in development of a drug as a substitute for statin drugs.
Cholesterol acyltransferase (hereinafter abbreviated as ACAT) is an enzyme which catalyzes the introduction of an acyl group into cholesterol, and it is considered to be a target of drugs which are expected to be developed for treatment of statin-resistant arteriosclerosis or tailor-made treatment in accordance with individual pathological conditions. This enzyme has attracted attention for years as an important target molecule of a drug for prevention and treatment of arteriosclerosis, and a number of synthetic ACAT inhibitors have been developed. However, these inhibitors have not yet been put to clinical use due to side effects or insufficient effects (Non-Patent Document 2).
It has recently been revealed that ACAT exists in the form of two isozymes, ACAT1 and ACAT2, which have different in vivo functions and different locations from each other (Non-Patent Document 3). ACAT1 is widely found in many living cells and tissues and is highly expressed particularly in macrofages and smooth muscle cells. It takes part in arteriosclerosis by causing the formation of foam macrofage cells, which are a cause of arteriosclerosis. ACAT2 is expressed specifically in the small intestine and liver and is thought to take part in the absorption of dietary cholesterol and the secretion of very low-density lipoproteins in each of these organs. As the difference between ACAT1 and ACAT2 with respect to in vivo functions becomes clear, the importance of specifying its selectivity has been recognized in the development of new drugs targeted at ACAT.
It has been found that synthetic ACAT inhibitors, the development of which has been abandoned, have an activity which selectively inhibits ACAT1 (such as Wu-V-23) or which inhibits both ACAT1 and ACAT2 (such as avasimibe and pactimibe) (Non-Patent Document 4).
Taking the recently reported results of knockout mice (Non-Patent Document 5) into consideration, there is a strong expectation that a new drug will be developed from the family of selective ACAT2 inhibitors. It is reported that pyripyropene A having the formula shown below (Non-Patent Document 6) is a selective ACAT2 inhibitor (Non-Patent Document 7). However, up to the present time, there has been no research aimed at development of a new drug which is a selective ACAT2 inhibitor.

It is disclosed in Patent Document 1 that pyripyropene derivatives in which the 1-, 7- and/or 11-positions of pyripyropene A are substituted by certain groups have an ACAT2-inhibiting activity. However, it is not disclosed or suggested in that document that ACAT2 inhibition is achieved without decomposition by metabolizing enzymes.    Non-Patent Document 1: Libby, J. Am. Col. Cardiol., Vol. 46, pp. 1225-1228, 2005;    Non-Patent Document 2: Meuwese et al., Cull. Opin. Lipidol., Vol. 17, pp. 426-431, 2006;    Non-Patent Document 3: Chang et al., Acta. Biochim. Biophys. Sin., vol. 38, pp. 151-156, 2006;    Non-Patent Document 4: Farese, Arterioscler. Thromb. Vasc. Biol., vol. 26, pp. 1684-1686, 2006;    Non-Patent Document 5: Bell et al., Arterioscler. Thromb. Vasc. Biol., vol. 27, pp. 1396-1402, 2007;    Non-Patent Document 6: Tomoda et al., J. Antibiot. Vol. 47, pp. 148-153, 1994;    Non-Patent Document 7: Lada et al., J. Lipid Res., vol. 45, pp. 378-386, 2004;    Patent Document 1: WO 2009/081957.